Han Jo Kim

Phase II Clinical Trial of Genexol (Paclitaxel) and Carboplatin for Patients with Advanced Non-small Cell Lung Cancer

Purpose This phase II clinical trial was conducted to evaluate the activity and safety of a combination treatment of paclitaxel (Genexol®) plus carboplatin in patients with advanced non-small cell lung cancer. Materials and Methods Chemotherapy-naïve patients having histologically confirmed advanced or metastatic non-small cell lung cancer were enrolled. Genexol® was administered at 225 mg/m2 intravenous (IV) infusion over 3 hours, followed by carboplatin (area under the concentration-time curve=6) IV on day 1 every 3 weeks. Results Twenty-eight patients were enrolled between January 2003 and January 2005. A total of 110 cycles of chemotherapy were given. The median number of chemotherapy cycles was 4. A total of 25 study patients were evaluable. On an intent-to-treat basis, there were ten partial responses (response rate 35.7%). The median time-to-progression was 3.2 months (95% confidence interval [CI], 1.5 to 4.9) and the median overall survival was 8.2 months (95% CI, 4.1 to 12.3). The main hematologic grade 3/4 toxicity was neutropenia, which was observed in 14 (50.0%) patients. The main non-hematologic toxicity was peripheral neuropathy, which was observed in 12 patients (42.9%). Grade 3/4 neuropathy occurred in 8 patients (28.6%) and three patients discontinued treatment because of neuropathy. Conclusion In this trial, the combination of Genexol® and carboplatin showed significant activity as first line treatment for patients with advanced or metastatic non-small cell lung cancer. However, a modest dose reduction of Genexol® is needed due to sensory neuropathy.

Hereditary hemorrhagic telangiectasia treated with low dose intravenous bevacizumab.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder that leads to mucocutaneous telangiectasias, epistaxis, and gastrointestinal bleeding. Depending on the severity and manifestation of the disease, various therapeutic modalities have been used, from local bleeding control to surgery or concomitant drug therapy. Several articles under review have presented guidelines for treatment of HHT with bevacizumab as a direct anti-angiogenesis strategy. Still, neither the exact optimal dose nor the minimum effective dose of intravenous bevacizumab in patients with severe HHT has been reported. A 55-year-old man presented with long-standing epistaxis, recent melena, dizziness, and a three-generation family history of chronic epistaxis, anemia, and regular blood transfusions. Treatment with argon plasma coagulation (APC) for the gastrointestinal bleeding failed to raise hemoglobin levels, we considered using the bevacizumab. We report a patient with severe HHT, who was treated with low-dose bevacizumab (2 mg/kg) and improved substantially.

A Prospective Multicenter Study Evaluating Secondary Adrenal Suppression After Antiemetic Dexamethasone Therapy in Cancer Patients Receiving Chemotherapy: A Korean South West Oncology Group Study

BACKGROUND In a previous pilot study, adrenal suppression was found to be common after antiemetic dexamethasone therapy in cancer patients. The objective of this large prospective multicenter study was to confirm the incidence and factors associated with secondary adrenal suppression related to antiemetic dexamethasone therapy in cancer patients receiving chemotherapy. METHODS Chemotherapy-naïve patients who were scheduled to receive at least three cycles of highly or moderately emetogenic chemotherapy with dexamethasone as an antiemetic were enrolled. Patients with a suppressed adrenal response before chemotherapy or those administered corticosteroids within 6 months of enrollment in the study were excluded. RESULTS Between October 2010 and August 2014, 481 patients receiving chemotherapy underwent the rapid adrenocorticotropic hormone (ACTH) stimulation test to assess eligibility; 350 of these patients were included in the final analysis. Fifty-six patients (16.0%) showed a suppressed adrenal response in the rapid ACTH stimulation test at 3 or 6 months after the start of the first chemotherapy. The incidence of adrenal suppression was affected by age, performance status, stage, and use of megestrol acetate in univariate analysis. Multivariate analysis revealed that secondary adrenal suppression associated with antiemetic dexamethasone therapy was significantly associated with megestrol acetate treatment (odds ratio: 3.06; 95% confidence interval: 1.60 to 5.86; p < .001). CONCLUSION This large prospective study indicates that approximately 15% of cancer patients receiving chemotherapy with a normal adrenal response show suppressed adrenal responses after antiemetic dexamethasone therapy. This result was particularly significant for patients cotreated with megestrol acetate.

Q787Q EGFR Polymorphism as a Prognostic Factor for Lung Squamous Cell Carcinoma

Objective: EGFR genetic polymorphisms have been investigated for carcinogenesis in various tumors including lung cancer. We evaluated EGFR mutations in four exons, with an emphasis on the Q787Q EGFR polymorphism in non-small-cell lung cancer. Methods: To determine the presence of the Q787Q polymorphism in patients with lung cancer, we performed direct sequencing analyses of four exons for 83 squamous cell carcinomas and 80 adenocarcinomas untreated with EGFR tyrosine kinase inhibitors. Results: The Q787Q EGFR polymorphism was more frequently detected in squamous cell carcinoma patients than in adenocarcinoma patients (24 vs. 15.9%). The group of patients with the Q787Q EGFR polymorphism included more males and heavy smokers compared with other patient groups. The presence of the Q787Q EGFR polymorphism significantly and negatively affected the overall survival rate among patients with non-small-cell carcinoma (p = 0.011), particularly those with squamous cell carcinoma (p = 0.037). Among stage I and II squamous cell carcinoma patients, those with the Q787Q EGFR polymorphism had a poor prognosis (p = 0.032). Conclusions: The Q787Q EGFR polymorphism allows stratifying lung squamous cell carcinoma patients and could be an independent prognostic marker, particularly among those in stages I and II.

RhoA is associated with invasion and poor prognosis in colorectal cancer.

Colorectal cancer is one of the most common cancers and is the fourth leading cause of cancer death in Korea. Mortality of colorectal cancer is strongly associated with the metastatic spread of the disease. As such, it is important to find and characterize signaling pathways involved in colon cancer metastasis. We investigated the functional importance of RhoA using human cell lines as well as 150 colorectal cancer patient-derived samples as it remains unclear whether RhoA functions as either an oncogene or a tumor suppressor in colon cancer. RhoA was highly expressed in metastatic cancer cell lines. Although cancer cell proliferation was only moderately impaired after depletion of RhoA, RhoA-depleted cancer cells exhibited markedly reduced migration and invasion ability in vitro. Furthermore, we found that RhoA is associated with the invasion of lymph nodes and blood vessels in the patient colorectal cancer samples. Most notably, patients with higher RhoA expression had a significantly poorer 5-year survival rate after surgery. These results suggest that RhoA is a marker of poor prognosis in colorectal cancer and may be a promising target for cancer treatment.

Upregulation of stromal cell-derived factor 1α expression is associated with the resistance to neoadjuvant chemoradiotherapy of locally advanced rectal cancer: Angiogenic markers of neoadjuvant chemoradiation

The ability to achieve pathologic downstaging after neoadjuvant chemoradiotherapy (NCRT) is correlated with improved survival in locally advanced rectal cancer (LARC). However, there is no effective predictive markers. In this study, the expression of angiogenic markers was evaluated in pre-treatment biopsies and corresponding post-treatment resection specimens, and were correlated to histopathological tumour characteristics and response. Fifty-five patients with stage II/III rectal cancer treated with 5-fluorouracil (5-FU)-based NCRT were studied. All patients were administered NCRT followed by surgical resection. Immunohistochemical staining for angiogenic markers [hypoxia-inducible factor 1α (HIF‑1α), vascular endothelial growth factor (VEGF), stromal cell‑derived factor 1α (SDF-1α) and placental growth factor (PlGF)] was performed on specimens obtained before NCRT and after surgery. Expression of VEGF, PlGF and HIF-1α protein was downregulated after NCRT in the rectal cancer tissues (P<0.001, P=0.001 and P=0.044, respectively). However, SDF-1α was upregulated after NCRT (P<0.001). Moreover, upregulated expression of SDF-1α (P=0.016) and positive PlGF staining (P=0.001) after NCRT were significantly associated with resistance to NCRT. On multivariate analysis, positive PlGF staining after NCRT was found to be independently associated with resistance to NCRT (P=0.013). Our data suggest that SDF-1α and PlGF should be evaluated as new targets for NCRT in LARC.

CORRIGENDUM: Correction of funding statement in ACKNOWLEDGEMENTS section: Epigenetic inactivation of RUNX3 in colorectal cancer

[This corrects the article on p. 19 in vol. 94, PMID: 29333422.].

Epigenetic inactivation of RUNX3 in colorectal cancer

Purpose Emerging evidence indicates that runt-related transcription factor 3 (RUNX3) is an important tumor suppressor gene in several cancer types, including colorectal cancer (CRC). However, the clinical significance of RUNX3 inactivation in CRC remains unclear. The aim of this study was to examine the correlation between clinicopathologic factors and RUNX3 hypermethylation/expression in CRC. Methods Sixty-two CRC patients who were treated at the Soonchunhyang University College of Medicine were recruited in this study. The hypermethylation of CpG islands in the RUNX3 promoter and the expression of RUNX3 mRNA were identified by methylation-specific polymerase chain reaction (PCR) and reverse transcriptase-PCR, respectively. The expression of RUNX3 was determined by immunohistochemical staining. Results Of the 62 CRC tissue samples, 20 (32.3%) presented hypermethylated RUNX3 promoters. Aberrant RUNX3 hypermethylation was found to be associated with vascular (P = 0.006) and lymphatic (P = 0.002) invasion. Hypermethylation of RUNX3 was associated with poor survival outcomes (P = 0.038). However, expression of RUNX3 was not a prognostic factor (P = 0.363). Conclusion Hypermethylation of RUNX3 may be a predictor of a poor prognosis in CRC.

Association Between c-Met and Lymphangiogenic Factors in Patients With Colorectal Cancer

Purpose Animal models show a strong relationship between lymphangiogenesis and lymph node metastasis. However, the clinical significance of lymphangiogenesis in patients with colorectal cancer (CRC) remains uncertain. This study aimed to evaluate the association between c-Met and lymphangiogenic factors and to elucidate the prognostic significance of c-Met in patients with CRC. Methods A total of 379 tissue samples were obtained from surgically resected specimens from patients with CRC at Soonchunhyang University Cheonan Hospital between January 2002 and December 2010. The expressions of c-Met, vascular endothelial growth factor (VEGF)-C, VEGF-D, VEGF receptor (VEGFR)-3, and podoplanin were examined using immunohistochemistry. The expression of c-Met and clinical factors were analyzed. Results Of the 379 tissues, 301 (79.4%) had c-Met expression. High expression of c-Met in tumor cells was significantly associated with high expression of VEGF-C (P < 0.001) and VEGFR-3 (P = 0.001). However, no statistically significant association with podoplanin (P = 0.587) or VEGF-D (P = 0.096) was found. Of the 103 evaluable patients, expression of c-Met in tumor cells was significantly associated with advanced clinical stage (P = 0.020), positive lymph node status (P = 0.038), and high expression of VEGF-C (P = 0.020). However, no statistically significant association with podoplanin (P = 0.518), VEGFR-3 (P = 0.085), VEGF-D (P = 0.203), or overall survival (P = 0.360) was found. Conclusion Our results provide indirect evidence for an association and possible regulatory link of c-Met with the lymphangiogenic markers, but c-Met expression in patients with CRC is not a prognostic indicator for overall survival.

The incidence of venous thromboembolism is not lowin Korean patients with advanced pancreatic cancer

Background Pancreatic cancer is among the most common malignancies associated with venous thromboembolism (VTE). Asian patients are known to have a lower incidence of VTE compared to Caucasian patients. However, few studies have investigated the incidence of VTE in Asian patients with pancreatic cancer. Methods This retrospective review of medical records was performed on 505 patients with histopathologically proven advanced stage pancreatic cancer, from January 2006 to December 2012, at Soonchunhyang University Hospitals. Results Ninety-four patients (18.6%) had at least one pulmonary embolism (PE), deep vein thrombosis (DVT), or splanchnic vein thrombosis (SVT); 38 patients had isolated SVT; and 56 patients (11.1%) had at least one classic VTE (PE and/or DVT of lower extremities). Patients with more advanced stages of pancreatic cancer (distant metastatic stage, recurrence) or who had received chemotherapy had a higher incidence of classic VTE. Patients who were simultaneously diagnosed with pancreatic cancer and classic VTE had a poorer prognosis than patients with subsequent VTEs. There was a significant difference in overall survival (OS) between the presence and absence of a concurrent classic VTE diagnosis (median: OS, 2.1 mo vs. 10.7 mo; P<0.001). Even when VTE included SVT, the result was similar (P<0.001). Conclusion In Korean patients with advanced pancreatic cancer, the incidence of VTEs is comparable to that of Caucasian patients. We also found that pancreatic cancer patients with concurrent VTEs had a poor prognosis compared to patients who developed VTEs later.